For almost 20 years, proton-gated cation channels have been known to exist in membranes of sensory neurons, where they are assumed to participate in nociception. Recently, several Acid Sensing Ion Channels (ASIC) have been cloned, and while some of these like ASIC3 (DRASIC) and ASIC-p are selectively expressed in sensory ganglia and/or the spinal cord, others, like ASIC1 and ASIC2, are expressed also in the brain [see e.g. Waldmann R, Champigny G, Bassilana F, Heurteaux C, Lazdunski M: A proton-gated cation channel involved in acid-sensing; Nature 1997 386 (6621) 173-177; Lingueglia E, De Weille J R, Bassilana F, Heurteaux C, Sakai H, Waldmann R, Lazdunski M: A modulatory subunit of acid sensing ion channels in brain and dorsal root ganglion cells; J. Biol. Chem. 1997 272 (47) 29778-29783; Bassilana F, Champigny G, Waldmann R, De Weille J R, Heurteaux C, Lazdunski M: The acid-sensitive ionic channel subunit ASIC and the mammalian degenerin MDEG form a heteromultimeric H+-gated Na+ channel with novel properties; J. Biol. Chem. 1997 272 (46) 28819-28822; Olson T H, Riedl M S, Vulchanova L, Ortiz-Gonzalez X R, Elde R: An acid sensing ion channel (ASIC) localizes to small primary afferent neurons in rats; NeuroReport 1998 9 (6) 1109-1113; Chen C-C, England S, Akopian A N, Wood J N: A sensory neuron-specific, proton-gated ion channel; Proc. Natl. Acad. Sci. USA 1998 95 (17) 10240-10245; and Coscoy S, de Weille J R, Lingueglia E, Lazdunski M: The pre-transmembrane 1domain of acid—sensing ion channels participates in the ion pore; J. Biol. Chem. 1997 274 (15)10129-10132].
The proton-gated channels cloned all belong to the amiloride-sensitive Na-channel/degenerin family of ion channels, and like for ionotropic purinergic receptors, the topology presumably is two transmembrane domains flanking a long extracellular loop.
Compounds inhibiting the proton-gated cation channels have been suggested useful for the treatment of pain.
WO 98/35034 discloses mammal neuronal acid sensing cationic channels, which are considered useful for screening for analgesic drugs and for the treatment of degeneration of periferic neurons
Since the demonstration that the level of extracellular glutamate in the brain is greatly elevated under ischaemia, much pharmaceutical research has been focused on design of glutamate receptor antagonists. There has, however, been discrepancy between in vitro and in vivo studies, especially with respect to the effect of antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. In vitro, neuro degeneration due to oxygen/glucose deprivation is blocked by the NMDA receptor antagonist MK-801, but not by α-amino-3-hydoxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. Strikingly, the case is opposite in in vivo models of global cerebral ischaemia: AMPA receptor antagonists reduces infarct volume, while NMDA receptor antagonists are ineffective.
Isatin derivatives like those described herein, for use as AMPA antagonists have been disclosed in e.g. WO 94/26747, WO 96/08494 and WO 96/08495. However, the use of these isatin derivatives as ASIC antagonising compounds have never been disclosed.